Project Summary/Abstract: The interferon-regulatory factor (IRFs) family of transcription factors (TFs) are central regulators of anti-viral responses. They translate signals from pathogen recognition receptors into complex transcriptional responses that are essential for viral control. Targeted genetic deletion of IRF TFs in mice increase susceptibility to viruses, which in turn have evolved mechanism to deactivate IRF signaling leading to increased virulence. Despite their importance, we still do not understand how IRFs coordinate the control of transcription to protect us from viruses. IRF TFs share structural homology in their DNA binding domains and bind highly similar DNA motifs. Yet, they regulate non-redundant antiviral transcriptional programs. The overall objective of this proposal is to determine how anti-viral IRF TFs act on a gene specific and genome wide scale to control anti-viral responses. The experiments in specific aim 1 will investigate why DENV, and not ZIKV, appears to stimulate IRF-1 and IFN? responses. Additional studies will test if the lack of IFN? response can help explain ZIKV neuropathology. Studies in specific Aim 2 will identify genome-wide networks of IRF gene activation and transcriptional signatures during DENV and ZIKV infections. Comparisons of responses in infected and uninfected neighboring cells will identify viral subversion of host cell signaling. Additionally, comparing responses in DENV and ZIKV infected cells will identify viral specific activation of IRF-dependent responses. Lastly, integration of genome-wide signal dependent and lineage determining TF binding and genomic features of active enhancers will help establish basic principals governing how IRFs cooperate with each other and other TFs to establish functional enhancers and control gene expression. Together this proposal will identify basic principals governing IRF regulation of viral responses and identify differences in viral specific IRF responses that may explain disease pathogenesis and advance treatments for these currently untreatable infections.